Atomic Mechanisms of Stabilizing and Destabilizing Co-Solvents on Protein Stability

Abstract

Urea and trimethylamine n-oxide (TMAO) are small molecules known to destabilize and stabilize, respectively, the structure of proteins when added to aqueous solution. To unravel the molecular mechanisms of these cosolvents on protein structure we perform explicit all-atom molecular dynamics simulations of extended poly-alanine and poly-leucine dimers. We use an umbrella sampling protocol to compute the potential of mean force (PMF) of dimers at different concentrations of urea and TMAO. We find that the large non-polar side chain of leucine is affected by both urea and TMAO whereas backbone atoms and alanine's side chain are not. Urea is found to occupy positions between leucine's side chains that are not accessible to water. This accounts for extra Lennard-Jones bonds between urea and side chains that provide the enthalpic driving force for unfolding.